Cachexia is a consequence of a variety of clinical disorders including cancer, AIDS and autoimmunity and is characterized by dramatic weight loss and muscle atrophy. The onset of cachexia is associated with a progressive and debilitating weakness leading to a dramatic decline in the quality of life of the patient. Therefore, treatment aimed at preventing cachexia in susceptible patients would not only improve the quality of life for these patients but is also likely to significantly improve responsiveness to therapy. Cachexia is often seen in conditions associated with immune deficiency and this has led us to speculate that a deficiency in the immune system might play a direct role in the development of cachexia, and that correcting or inhibiting the immune deficiency might allow protection from cachexia. To test this hypothesis we have used three mouse models of cachexia that are associated with lymphopenia: i) diabetes-induced cachexia using the NOD mouse [the NOD mouse is a well-established mouse model for insulin-dependent diabetes mellitus (IDDM)], and ii) the rapidly progressing cancer cachexia model induced in the C57BL/6 mouse strain by Lewis Lung Carcinoma (LLC) cells, and iii) the well-established and more slowly progressing cancer cachexia model induced in the BALB/c mouse with colon-26 (C-26) cells. We have shown that infusion of highly purified CD4+ CD44V low cells, but not CD4+ T cells depleted of CD4+ CD44V low cells, into either pre-diabetic mice or into mice that already have profound tumor growth, causes a significant inhibition in the onset of cachexia. In order to substantiate this finding we will test the hypothesis that CD4+ CD44V low cells also reverse cachexia in the well-established C-26-induced cancer cachexia model (Specific Aim 1). We have also shown that protection from cachexia by the infusion of CD4+ CD44V low cells is associated with inhibition of CD4+ T cell lymphopenia. In Specific Aim 2 we will test the hypothesis that CD4+ CD44V low cells inhibit CD4+ T cell lymphopenia by undergoing proliferation and differentiation into memory cells, and in Specific Aim 3 we will test the hypothesis that the ability of CD4+ CD44V low cells to protect against cachexia is dependent on their ability to inhibit lymphopenia. In the long term it is hoped that the information gained might be used for the design of new treatments to reverse and/or inhibit cachexia in patients with cancer. [unreadable] [unreadable]